Natural Health Products for Anti-Cancer Treatment: Evidence and Controversy

Natural Health Products (NHPs) have long been considered a valuable therapeutic approach for the prevention and treatment of various diseases, including cancer. However, research on this topic has led to inconclusive and often controversial results. This review aims to provide a comprehensive update of the effects and mechanisms related to the use of NHPs, to describe the results of randomized clinical trials (RCTs) on their effects in cancer patients, and to critically discuss factors influencing clinical outcomes. RCTs available in the literature, even those studying the same NHP, are very heterogeneous in terms of indications, doses, route and timing of administration, and outcomes evaluated. Silymarin, ginsenoside, and vitamin E appear to be useful in attenuating adverse events related to radiotherapy or chemotherapy, and curcumin and lycopene might provide some benefit in patients with prostate cancer. Most RCTs have not clarified whether NHP supplementation provides any real benefit, while harmful effects have been shown in some cases. Overall, the available data suggest that although there is some evidence to support the benefits of NHPs in the management of cancer patients, further clinical trials with the same design are needed before their introduction into clinical practice can be considered.


Introduction
Natural Health Products (NHPs), such as dietary supplements, probiotics and vitamins, belong to the group of unconventional practices called Complementary and Alternative Medicine (CAM).
CAM is considered a valuable approach in several clinical settings because of its alleged ability to positively influence the response to drug therapy in terms of efficacy and safety and to improve patients' quality of life (QOL) [1][2][3].
In the continuously evolving landscape of cancer treatment, NHPs have garnered considerable attention as potential therapeutic agents for cancer treatment, either as single agents or in combination with conventional therapies.NHPs are usually obtained from plants, marine organisms and microorganisms, and display a wide range of chemical structures with different pharmacological activities [4].These include the inhibition and modulation of tumorigenic pathways involved in cancer pathogenesis such as cell proliferation, angiogenesis, metastasis and apoptosis evasion.Moreover, most of these compounds have a relatively low toxicity profile.As a result, their characteristics makes them attractive candidates for therapeutic development [5].Polyphenols, alkaloids, flavonoids and terpenoids are the most extensively studied NHPs that, due to their diverse chemical structures and biological activities, have shown promising anti-cancer properties in preclinical studies and early-phase clinical trials [6].Several randomized clinical trials (RCTs) have been conducted using NHPs to improve the efficacy of radio-chemo-immuno-based therapy and to mitigate related side effects or protect normal cells from iatrogenic toxicity (Figure 1).However, mixed and inconclusive results have been reported [7][8][9][10].
proliferation, angiogenesis, metastasis and apoptosis evasion.Moreover, most o compounds have a relatively low toxicity profile.As a result, their characteristics them attractive candidates for therapeutic development [5].Polyphenols, alk flavonoids and terpenoids are the most extensively studied NHPs that, due t diverse chemical structures and biological activities, have shown promising antiproperties in preclinical studies and early-phase clinical trials [6].Several rando clinical trials (RCTs) have been conducted using NHPs to improve the efficacy of chemo-immuno-based therapy and to mitigate related side effects or protect norm from iatrogenic toxicity (Figure 1).However, mixed and inconclusive results hav reported [7][8][9][10].
Variations in study design, patient characteristics, dosage and formulation of n products, concomitant treatments and outcome measures have negatively influenc results of the RCTs.Consequently, a thorough analysis of factors influencing outcomes is essential to accurately interpret study findings and to pave the w personalized treatment approaches that incorporate NHPs into cancer therapy.In this review we aim to provide a comprehensive update of the effec mechanisms related to the use of NHPs in cancer, to describe the results of rando clinical trials (RCTs) available in the literature in the last two decades, and to pro critical analysis of the factors influencing clinical outcomes critically evaluating the of these factors on the interpretation of RCTs.Variations in study design, patient characteristics, dosage and formulation of natural products, concomitant treatments and outcome measures have negatively influenced the results of the RCTs.Consequently, a thorough analysis of factors influencing clinical outcomes is essential to accurately interpret study findings and to pave the way for personalized treatment approaches that incorporate NHPs into cancer therapy.
In this review we aim to provide a comprehensive update of the effects and mechanisms related to the use of NHPs in cancer, to describe the results of randomized clinical trials (RCTs) available in the literature in the last two decades, and to provide a critical analysis of the factors influencing clinical outcomes critically evaluating the impact of these factors on the interpretation of RCTs.

Investigating the Efficacy and Mechanisms of NHPs in Enhancing Cancer Radiotherapy
Radiotherapy is a cornerstone of cancer treatment that uses ionizing radiation to induce DNA damage, triggering tumor cell death.While effective, radiotherapy can inadvertently damage surrounding healthy tissues, leading to differential adverse events [11,12].Recent preclinical and clinical studies have clearly demonstrated that NHP supplementation to radiotherapy can potentially increase treatment efficacy (radiosensitizing effects) or protect normal cells from radiation-induced damage (radioprotective effects), improving patients' clinical outcomes [13].In particular, some NHPs have been shown to exhibit potent radiosensitizing effects acting on key molecular pathways involved in tumor radioresistance and regulation of cell proliferation, DNA damage, survival, induction of apoptosis, and cellular responses to stress and inflammation including PI3K/Akt/mTOR, miR-34a/Sirt1/p53, MAPK and NF-kB pathways [14][15][16].Among the various natural compounds, curcumin (a polyphenolic compound derived from turmeric Curcuma longa), resveratrol (a stilbenoid compound derived from grapes, berries or peanuts), epigallocatechin-3-gallate (EGCG) (the predominant catechin in green tea) and quercetin (a potent antioxidant flavonoid plant pigment) have been shown to inhibit PI3K/Akt/mTOR and NF-kB pathways, significantly increasing radiotherapy-induced cancer cell death [13,[16][17][18][19][20][21][22].In addition, besides inducing apoptosis through the PI3K/Akt/mTOR and NF-kB pathways, EGCG and curcumin could also exert radiotherapy-induced cancer cell death by activating the miR-34a/Sirt1/p53 signaling pathway or inhibiting the MAPK pathway, respectively [13].All of these compounds, along with others, also showed a potent radioprotective effect by promoting DNA damage repair and anti-oxidant/anti-inflammatory activity [11,13].Specifically, curcumin, resveratrol, EGCG, quercetin, apigenin (a natural plant flavonoid found in parsley, celery or chamomile tea) and genistein (an isoflavone derived mainly from soy) have been shown to promote DNA damage repair and integrity through activation of DNA repair enzymes and attenuation of oxidative stress, respectively [11,13].In contrast, astragalus and schisandra (polysaccharides isolated from Astragalus membranaceus and Schisandra chinensis [23], Hoehenbuehelia serotina (a species of fungus), ginsenoside and acanthopanax senticosus (saponins derived from ginseng), matrine, ligustrazine and β-carboline (alkaloids derived from Ligusticum chuanxiong, Peganum harmala and Banisteriopsis caapi) [11,13], vitamin C (primarily found in oranges, lemons, kiwi, strawberries, peppers, broccoli and cabbage) and E (present in oily nuts, almonds, wheat germ oil and vegetable oils), selenium (an essential trace element found in foods like Brazil nuts, tuna, chicken, turkey, beans, lentils and eggs) and carotenoids (found in carrots, spinach, pumpkin, melons and tomatoes) have a recognized ability in scavenging free radicals generated by ionizing radiation [6].Finally, curcumin, genistein, hesperidin (a flavonoid found in citrus fruits), ferulic acid (a phenolic compound found in grains, fruits and vegetables) and caffeine (found in coffee or tea) have been linked to down-regulation of inflammatory cytokines or inflammatory mediators, including TNF-α, IL-6, IL-12 and Cox-2, thereby reducing radiotherapy-induced inflammation [11,13].

Synergistic Enhancement of Cancer Chemotherapy by NHPs: Mechanisms and Clinical Implications
Chemotherapy, a widely used cancer treatment, relies on cytotoxic drugs that target rapidly growing cancer cells.However, chemotherapy often induces systemic toxicity and drug resistance, limiting its effectiveness [24].Preclinical studies and clinical trials have shown that NHPs integrated into chemotherapy regimens can enhance the tumorkilling effect by reducing the development of drug resistance (chemosensitization effects) or mitigate chemotherapy-induced side effects (chemoprotective effects).Several natural compounds have been shown to exert potent chemosensitization effects by inhibiting inflammation, tumor proliferation and angiogenesis, as well as inducing apoptosis/necrosis and autophagy of cancer cells [25].For example, curcumin, resveratrol, naringin (a natural bioflavonoid derived from grapefruit or other citrus fruits) and berberine, an isoquinoline alkaloid found in several medicinal plants, including Berberis vulgaris, Coptis chinensis, Hydrastis Canadensis, and Berberis aristata [26], can inhibit the expression of Cox-2 and NF-kB, both involved in inflammatory signaling pathways [27,28].Curcumin, resveratrol, naringin and berberine can also block cell division by inhibiting cyclin-dependent kinases (CDKs) and other cell-cycle regulatory proteins [27][28][29].They can also restrain the secretion of vascular growth factors and components of the signaling pathway involved in angiogenesis [28].Curcumin, resveratrol, naringin and berberine have been shown to inhibits growth factor receptors, thereby sensitizing cancer cells to apoptosis induction [28].On the other hand, Solanum nigrum Linn.(a medicinal plant) and hederagenin (a triterpenoid isolated from Hedera helix) can promote the conversion of LC3 (microtubule-associated proteins 1A/1B light chain 3B) from its cytosolic form (LC3-I) to its lipidated form (LC3-II), thereby facilitating the formation of autophagosomes [30,31].
The chemoprotective effects of NHPs are related to their free-radical scavenger properties, ability to inhibit components of the inflammatory pathway or apoptosis induction, activation of cholinergic neurotransmission and stimulation of bone marrow cells, and a neuroprotective and cardioprotective role.In particular, gingerol (a phenolic phytochemical compound found in fresh ginger) and silymarin (a mixture of flavonolignans isolated from milk thistle plant Silybum marianum) may reduce chemotherapy-induced liver damage by scavenging free radicals and inhibiting inflammatory pathways [35,36].Gingerol seems also able to combat chemotherapy-induced nausea, vomiting, myalgia and insomnia by acting on serotonin release and on cholinergic (M3) receptor activities [37,38].Berberine, tanshinone IIA (a lipophilic active constituent isolated from Salvia), geraniol (a monoterpenoid alcohol present in essential oils) and thymoquinone (a benzoquinone isolated from Nigella sativa) could contrast chemotherapy-induced neurotoxicity and neuroinflammation by inhibiting the expression of apoptosis-related proteins (p53, MAPK, etc.) in neuronal cells and increasing brain AchE activity [32].Thymoquinone, as reported for curcumin and resveratrol, could attenuate chemotherapy-induced nephrotoxicity by increasing the NAD+ dependent Sirt1, which in turn reduces the activation of the chemotherapy-associated p53 acetylation and apoptosis induction [32].Ginsenoside Rg3 (a triterpenoid saponin found in ginseng) can mitigate chemotherapy-induced bone marrow suppression by promoting the proliferation of total spleen and bone-marrow cells (BMCs) [39].Hesperidin is reported to reduce diarrhea-related chemotherapy by inhibiting the expression of inflammatory factors, as well as by suppressing STAT3 activity in intestinal tissues [32].Finally, quercetin, silymarin, calycosin (an isoflavone found in Astragalus membranaceus), hydroxytyrosol (olive oil phenolic antioxidant) and colchicine (an alkaloid extracted from Colchicum and found in corn, seeds or flowers) can exert a cardioprotective role on chemotherapy effect by inhibiting the NLRP3-cystatin-1-GSDMD pathway and oxidative stress in cardiomyocytes [32,40].

Unveiling the Potential of Natural Compounds in Boosting Immunotherapy: Mechanisms and Clinical Implications
Immunotherapy has emerged as a revolutionary approach in cancer treatment, harnessing the body's immune system to target and eliminate cancer cells.Despite its notable successes in specific cancer types, persistent challenges include limited response rates and the occurrence of immune-related adverse events [41][42][43].To date, there are a limited number of preclinical studies or early-phase clinical trials evaluating the effect of NHPs in combination with immunotherapy.These studies have shown that NHPs have the potential to enhance and reduce, respectively, the efficacy and toxicity of immunotherapy through immunomodulating activity.Specifically, curcumin, ginseng, astragalus membranaceus extracts, quercetin, gambogic acid (a flavonoid compound extracted from the resin of the Garcinia hanburyi) and baicalin (a flavone glycoside extracted from Scutellaria baicalensis) have been shown to increase immune cell infiltration into tumors and boost T, B, dendritic and natural killer (NK) cell activity by promoting the production of cytokines (e.g., IL-6, IL-12, TNF-α and IFN-γ) or antibodies, as well as down-regulating immune checkpoints (e.g., CTLA-4, Foxp3 or PD-L1), thereby inhibiting tumor progression and metastasis [44][45][46].On the other hand, these compounds can also exert an immunosuppressive effect by inhibiting regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) by reducing the production of immunosuppressive cytokines (e.g., IL-10 and TGFß) or the activation of STAT3 signaling [44], respectively.Consequently, by modulating inflammatory responses, these compounds have also been associated with the attenuation of inflammatory damage to healthy tissues resulting from generalized immune activation.Similarly, plantain polysaccharide (PLP), extracted from the whole plant of Plantago asiatica L., has been shown to promote dendritic cell maturation, M1 phenotype macrophage polarization and intratumoral matrix remodeling by modulating cytokine release (e.g., IL-12 p70, TNF-α, IL-1β, and IL-6), M1 surface molecule expression (e.g., CD80 and CD86) and nitric oxide production, respectively [45].

Vitamins and Other Micronutrients in Cancer Patients
Vitamins and other micronutrients are frequently used by patients with hematologic malignancies and solid tumors [47].
Vitamin E is a fat-soluble vitamin of the Tocotyol family (including four tocopherols and four tocotrienols).These compounds have the role of protecting the integrity of cell membranes by inhibiting lipid peroxidation and acting as antioxidants.They are also involved in maintaining neurological structure and function, and they protect red blood cells from lysis caused by irradiation [48][49][50].Vitamin C is involved in several physiological processes, mainly due to its electron-donating property.It plays an important role in protection from reactive oxygen species (ROS), prevention of endothelial dysfunction, modulation of gene transcription and DNA methylation [51].Cancer patients often have lower plasma levels of vitamin C than healthy subjects.For this reason, several RCTs have been designed to evaluate the potential anticancer effect of vitamin C supplementation.As early as the 1970s, Cameron and Linus Pauling showed that high doses of intravenous and oral vitamin C significantly prolonged the survival of patients with terminal cancer [52].Subsequently, two RCTs, based on oral administration, failed to reproduce similar results; rather, they showed no beneficial effects of high-dose vitamin C against advanced malignancies [53,54].However, these two clinical studies are not at all comparable with the first one, mainly because of the route of administration.Indeed, intravenously administered vitamin C can reach higher plasma levels (about 70-fold) than that orally administered [55].
As with vitamin C, the effects of vitamin D have been studied on the assumption that its low circulating levels have been correlated with increased cancer risk [56].Indeed, several studies have shown potential antitumor effects of vitamin D supplementation in colorectal, breast, pancreatic, ovarian, and prostate cancers.In addition, because vitamin D acts as a regulator of immune system processes, it has been suggested that it might sensitize cancer immunotherapy [56].However, a recent meta-analysis including 14 RCTs with 104,727 participants using vitamin D supplementation failed to found a statistically significant effect in reducing cancer mortality [57].
Selenium is an essential mineral incorporated into selenoproteins, which, like vitamins, are involved in the body's antioxidant defense mechanisms.Furthermore, in the immune system, selenium stimulates the formation of antibodies and the activity of T helper cells, cytotoxic T cells and Natural Killer (NK) cells [58].Several studies have been conducted to evaluate possible benefits of selenium supplementation in cancer based on the assumption that observational studies have found that high circulating levels of selenium are associated with a lower risk of cancer in the general population [59].However, RCTs have mostly failed to confirm the existence of these protective effects [60], suggesting, rather, an increased risk of developing specific neoplasms such as high-grade prostate cancer [61].

Randomized Controlled Trials of Natural Health Products in Cancer Patients
Tables 1 and 2 report the characteristics and main results of RCTs available in the literature over the past two decades that have tested the effects of herbal supplements (Table 1) and vitamins and other micronutrients (Table 2) in different types of cancer.Among herbal supplements, RCTs have been carried out to study the potential anticancer effects of agents such as resveratrol, genistein, ginsenoside, silymarin and curcumin.
Genistein and ginsenoside have been reported to play a positive role in prostate and breast-cancer patients, respectively.Lazarevic et al. studied the possible role of supplementation with synthetic genistein used at a dosage of 30 mg for 3-6 weeks before prostatectomy.They reported a significant reduction (p = 0.051) in serum PSA levels in patients who received genistein compared with the placebo group, in which PSA increased by 4.4 percent [63].In breast cancer patients, the RCT by Hamidian et al. evaluated the potential role of Panax ginseng, containing ginsenoside, in attenuating doxorubicin-induced cardiac toxicity.A significant protective role was found in patients supplemented with 1 g daily after four and eight cycles of chemotherapy (p < 0.001) [64].In contrast, another RCT that evaluated the potential effects of Panax ginseng (400 mg twice daily for 28 days) in reducing fatigue in patients with various advanced malignancies (including breast cancer) found no differences in outcomes among patients who received such supplementation compared with placebo [65].Finally, supplementation with 500 mg daily of Panax ginseng was protective (supplemented patients vs. placebo, p < 0.001) against radioiodine therapyinduced genotoxicity in patients with thyroid cancer [66].
No evidence of beneficial effects emerged from RCTs using resveratrol.In contrast, in patients with colorectal/hepatic metastases, administration of 5 g of micronized resveratrol daily has been correlated with the possible occurrence of gastrointestinal adverse events such as nausea and diarrhea and, less frequently, other adverse events including chills, lethargy, rash, skin irritation, and vascular redness [62].
Numerous examples of evidence have been accumulated from RCTs on the use of silymarin in the management of radio-and chemotherapy-related adverse events.Silymarin is a molecule extracted from Silybum marianum, known for its antioxidant, anti-inflammatory and hepatoprotective activities [131].
In breast cancer patients, daily oral administration of silymarin 140 mg appears to alleviate hepatotoxicity related to the doxorubicin/cyclophosphamide/paclitaxel chemotherapy regimen (p = 0.012) [67].In patients with the same type of cancer, the use of 1% silymarin gel once daily appears to delay and attenuate the severity of radiotherapy-induced dermatitis (p < 0.05) [68].
Similar effects were reported in patients with head and neck cancer supplemented with silymarin (at a dosage of 420 mg daily).Such supplementation was able to reduce radiotherapy-related mucositis during 6 weeks of radiotherapy (p < 0.05) [69].
Elyasi et al. reported that a 1% gel of silymarin twice daily delayed the onset and reduced the grade of severity of capecitabine-related hand-foot syndrome in patients with colorectal and esophagogastric patients [70].In contrast, Shahbazi F. et al. reported no efficacy for silymarin (420 mg daily, divided into three doses during chemotherapy) in the management of nephrotoxicity caused by cisplatin in patients with upper gastrointestinal (75%) and ovarian (21%) cancer and patients with mesothelioma (4%) [71].
Curcumin has also been studied to evaluate its protective role against radiotherapy toxicity.The RCT by Talakesh et al. found no significant effects in attenuating the severity of radiation-induced skin reactions in breast cancer patients who received 80 mg daily of curcumin compared with the placebo group during the first-to-sixth weeks of treatment.However, the difference between the intervention and placebo groups became significant after seven weeks of treatment (p = 0.01) [74].In breast cancer, even a dosage of 6 g per day, tested by Ryan et al. with regard to the effect of reducing radiation-induced dermatitis, was not associated with any benefit [77].
In studies conducted in prostate cancer patients who received 3 g daily of curcumin, an increase in total antioxidant capacity (TAC), without altering the therapeutic efficacy of radiotherapy, was demonstrated compared with the placebo group (p < 0.05) [78].Furthermore, in patients with prostate cancer undergoing intermittent androgen deprivation (IAD), it has been shown that oral supplementation of curcumin was associated with stopping the increase in PSA values (p = 0.02) [75].In head and neck cancer, the use of 0.1% curcumin for buccal washes has been shown to be insufficient to prevent, but helpful in delaying, the onset of radiation-induced oral mucositis [73].
Lycopene is a natural antioxidant belonging to the carotenoid family and found in red and yellow fruits or plants, especially tomatoes [132].A number of studies have tested the potential benefits of lycopene-containing dietary supplements in patients with prostate cancer [132,133].
Kucuk et al. evaluated the effects of a tomato oleoresin extract containing 30 mg of lycopene for 3 weeks in 26 male patients with clinical stage Tl or T2 prostate cancer before radical prostatectomy.After surgery, subjects in the intervention group had smaller tumors, less involvement of surgical margins and/or extra-prostatic tissues with cancer, and less widespread involvement of the prostate by high-grade prostatic intraepithelial neoplasia than the control group.PSA was lower in the intervention group than in the controls [79].
In contrast, Clark et al. failed to demonstrate clinical efficacy for daily lycopene supplementation with 15, 30, 45, 60, 90, and 120 mg/day for 1 year.No serum PSA response was observed but, rather, 37% of patients had increased levels of PSA [82].Mariani et al. also found no beneficial effects for lycopene supplementation, at a dosage of 20-25 mg/day for six months in prostate cancer patients with high-grade prostatic intraepithelial neoplasia [81].
Clinical studies have reported an association for lycopene and other components of the Mediterranean diet with reduced occurrence and progression of colon cancer [134].The RCT by Walfisch et al. studied in colon cancer patients who were candidates for colectomy the potential effects of oral lycopene integration in reducing plasma levels of insulin-like growth factor-I (IGF-I), a recognized risk factor for various cancers including colon cancer.The authors reported that lycopene extract taken with meals at a dosage of 30 mg twice daily for a variable period of time before surgery played a preventive role, reducing the plasma concentration of IGF-I by about 25% compared with the placebo group (p < 0.05) [80].
Several RCTs have examined the role of vitamin E in preventing neurotoxicity of chemotherapy regimens and relieving xerostomia and mucositis associated with radiotherapy.
Argyriou et al. and Pace et al. [83,85] showed that treatment with vitamin E (600 mg/day and 400 mg/day, respectively) in patients with solid tumors receiving cisplatin-based chemotherapy resulted in a reduction in the incidence of chemotherapy-induced peripheral neuropathy (CIPN) compared with patients who received placebo (p = 0.026 and p < 0.01, respectively).Argyriou et al. also showed that vitamin E (300 mg twice daily) protected cancer patients from the occurrence of paclitaxel-induced peripheral nerve damage [86].
A large study [87] conducted in patients with nonmyeloid solid tumors (n = 140) showed that recovery from CIPN was faster in the group of patients receiving taxanebased chemotherapy treated with vitamin E (400 mg twice daily) than in the control group (p = 0.01), suggesting that vitamin E might reduce the duration of CIPN.
Similarly, the studies by Afonseca et al. [88], Salehi et al. [89] and Kottschade et al. [90], finding no differences between the vitamin E-supplemented and placebo groups, questioned the benefits of this NHP supplementation in preventing CIPN.
The absence of a clear benefit, as in the study by Afonseca et al., could be due to the administration of vitamin E in combination with other substances (e.g., calcium and magnesium).This may have interfered with the vitamin's antioxidant activity, making it less effective in preventing the peripheral neuropathy.Another concern relates to dosage; in fact, the daily dose of vitamin E used in the different RCTs ranged from 300 to 800 mg/day.The studies by Heiba et al. and Kottschade et al. [87,90], which enrolled the largest number of patients (n = 140 and n = 189, respectively), despite administering the highest dose, found no benefit.
Another form of neurotoxicity is ototoxicity, which is strongly associated with cisplatinbased chemotherapy.In this regard, it has been shown that vitamin E (400 mg/day) may also have a neuroprotective role, preventing hearing loss in patients with solid tumor treated with cisplatin-based chemotherapy compared with those in the control arm [92].
Vitamin E has also been evaluated for its efficacy in improving radiotherapy-induced oral symptoms such as xerostomia and mucositis.Ferreira et al. [91] demonstrated that rinsing the oral cavity in an oil solution containing vitamin E decreased the incidence of symptomatic oral radio-induced mucositis in patients with head and neck cancer.Chung et al. [105] reported that oral supplementation of vitamin E and C (100 IU vitamin E plus 500 mg vitamin C twice daily during radiotherapy) in patients with head and neck cancer improved xerostomia assessed at 1 month and 6 months after treatment (p = 0.008, and p = 0.007, respectively) compared with the control group.
Few RCTs, which are variable in cancer type, administration route and evaluated outcomes, have studied the potential benefits of vitamin C supplementation.The most important positive effects of vitamin C in terms of remission (p = 0.004) and overall survival (p = 0.039) in the supplemented group compared to the placebo group were found in the RCT of Zhao et al. [93], in which vitamin C was used intravenously at low doses in elderly patients with acute myeloid leukemia treated with decitabine-based chemotherapy.
Considering again hematologic cancers, in the study of van Gorkom et al. [94], patients with myeloma or lymphoma requiring autologous hematopoietic stem cell transplantation (HSCT), who are often vitamin C deficient, received intravenous vitamin C every 24 h until the day of discharge.After discharge, patients in the intervention group received oral vitamin C. Unfortunately, OS at 3 months, neutrophil recovery time, hospitalization time, and incidence of neutropenic fever did not differ between the intervention groups and placebo group.
Similarly, a large study (n = 442) [95] performed in patients with metastatic colorectal cancer (mCRC) treated with FOLFOX ± bevacizumab chemotherapy failed to show that high-dose vitamin C can increase Patient Free Survival (PFS) and OS compared with chemotherapy alone.However, the same study showed that supplementation can benefit patients with mCRC carrying the RAS mutation.Evaluation of adverse events according to CTCAE (v.4.0) showed no clinically significant additional toxicity in the intervention arm compared with the placebo arm.
The study by Ma et al. [96] also evaluated the safety profile of high-dose intravenous vitamin C supplementation over a long follow-up of 5 years and in patients with stage III or IV ovarian cancer treated with carboplatin and paclitaxel.The study showed that vitamin C treatment did not increase the rate of grade 3 or 4 toxicities.However, mild-to-moderate grade toxicities were significantly less frequent in the intervention group than in the placebo group (p < 0.0001 and p = 0.003, respectively).
Oral administration of vitamin C in patients with cancer has been evaluated in RCTs that evaluated changes in various molecular factors.Mild protective effects in modulating inflammation have been reported in patients with esophageal adenocarcinoma undergoing radiotherapy, chemotherapy (5-fluorouracil and cisplatin) and surgery [98].
In addition, results of the study by Gilberg et al. [97] suggest that normalization of plasma vitamin C by oral supplementation in patients treated with 5-azacytidine may increase levels of the 5-methylcytosine (5 mC) and 5-hydroxymethylcytosine (5 hmC) ratio compared to patients treated with placebo, thereby enhancing the effects of 5-azacitidine.
Tumor type, route of administration, and dosage may influence the efficacy of vitamin C treatment.In van Gorkom's study [94], for example, patients with myeloma or lymphoma in the active intervention group received intravenous vitamin C every 24 h until the day of discharge.However, after discharge, vitamin C was given orally.
In the large study by Wang et al. [95], however, patients with mCRC received highdose intravenous vitamin C only for 3 days of each chemotherapy cycle, which may not be enough for vitamin C to exert its antitumor effect.Moreover, because supplementation was stopped at 6 months before most patients progressed, the impact of vitamin C on the tumor may be underestimated.In addition, the frequency of vitamin administration may also be important, as demonstrated in a mouse model by Campbell et al., who observed that the antitumor activity of ascorbate was greater after daily administration compared with infusions every other day [134].
Many patients take solutions containing vitamin mixes, the so-called multivitamins, with antioxidant activity during cancer therapy in order to improve outcomes or alleviate adverse effects of chemotherapy.RCTs that have evaluated the efficacy and safety profile of these supplements include the study of Bairati et al. [102], which investigated vitamin E and beta-carotene supplementation on head and neck cancer patients treated with radiation therapy.The supplements were administered during radiotherapy and for an additional 3 years.Contrary to expectations, cause-specific mortality rates tended to be higher in the intervention arm than in the placebo arm.
Similarly, Meyer et al. [103] tested the effects of oral supplementation of vitamin E and beta-carotene on the outcomes of smoking patients with head and neck cancer undergoing radiation therapy.Again, the intervention group demonstrated higher recurrence (p = 0.03), early mortality (p = 0.04) and all-cause mortality (p = 0.02) compared with the placebo group, leading to the hypothesis that the combined exposures of smoking and supplementation reduced the efficacy of radiotherapy.
The benefits of vitamin E and beta-carotene supplementation along with vitamin C were also evaluated in patients with stage IIIb and IV NSCLC treated with paclitaxel-and carboplatin-based chemotherapy, without finding significant differences in overall survival (OS) at one and two years (p =0.20) between the intervention and control arms [104].
Unlike previous studies, Cascinu et al. [106] measured cell proliferation in colon mucosa of patients with resected colorectal cancer using proliferating cell nuclear antigen (PCNA) after 6 months of oral supplementation with vitamin C, vitamin E, vitamin A and calcium.
The difference in the percentage of reduction of mean PCNA marking index (PCNALI) between baseline and 6 months after supplementation showed a decrease in both the intervention and placebo arms (p = 0.0001), suggesting that calcium and vitamin supplementation did not reduce the cellular kinetics of the colonic epithelium.
In conclusion, most RCTs have failed to demonstrate the real benefits of multivitamin supplementation in cancer patients; in fact, in several cases it has even been shown to be harmful.Among the few studies in favor of supplementation, the RCT by Suhail et al. [107] showed that co-administration of vitamins C and E in women with breast cancer restored antioxidant status (lowered by the presence of the tumor itself and chemotherapy) and reduced DNA damage, suggesting that these vitamins might be useful in protecting against chemotherapy-related side effects.
The effects of selenium supplementation (alone or in combination with vitamins) have been studied in patients with various malignancies.
Selenium is an essential mineral incorporated into selenoproteins, which, like vitamins, are involved in the antioxidant defense mechanisms.Furthermore, in the immune system, selenium stimulates the formation of antibodies and the activity of T helper cells, cytotoxic T cells and NK cells [58,135].
The antitumor activity of selenium has been mainly attributed to its ability to interfere with the synthesis of active redox proteins and, in general, to modulate cellular redox balance [136].
In the study of Rocha et al., an oral selenium supplementation for 60 days (at doses ranging from 27 to 100 mcg) alleviated treatment toxicities such as neutropenia and increased immunoglobulin A synthesis in patients with leukemia and solid tumors [109].The combination of selenium and zinc in oral tablets administered for 50 days has also been shown to alleviate treatment-related asthenia and improve appetite in patients with gastrointestinal cancers [129].Karp et al. investigated the incidence of second primary cancer in 1040 patients with Non-Small-Cell Lung Cancer (NSCLC) after a long follow-up of 7.9 years.No difference between patients who received 200 mcg daily of selenium or placebo was found [111].In addition, a decrease in oxidative stress caused by iodine treatment, as measured by the detection of reduced concentrations of 8-epi-PGF2α, was evidenced after administration of 400 mcg selenium, combined with 2000 mg vitamin C, and 1000 mg vitamin E, given to patients for 21 days prior to therapy in patients with thyroid cancer [124].
Fuchs-Tarlovsky et al. evaluated the potential effects of an oral supplement containing selenium 15 mcg combined with beta-carotene 4.8 mg; vitamin C, 200 IU; and vitamin E, 200 IU, on hematological toxicity, QOL, and oxidative stress in patients with cervical cancer treated with radiotherapy and cisplatin-based chemotherapy.The authors found that NHP supplementation induced a trend toward reduced oxidative stress and maintained hemoglobin levels at a value of 12.50 ± 1.22 g/dL.In addition, QOL was significantly increased in the supplemented group compared to the placebo [123].
The study of Hopkins et al. evaluated the effects of 200 µg L-selenomethionine combined with several other antioxidant micronutrients, including 800 mg DL-α-tocopherol acetate, 24 mg β-carotene, 1.0 g vitamin C, 7.2 mg riboflavin, 80 mg niacin, 60 mg zinc, and 5 mg manganese administered daily for 4 months, in influencing levels of oxidative and inflammatory biomarkers in patients with a history of sporadic colorectal adenoma.Plasma concentration of TNF-α and cystine significantly decreased in the active treatment group by 37% (p = 0.002) and 19% (p = 0.03) compared with the placebo group.The decreases in TNF-α and cystine were more pronounced in nonsmokers [126].

Factors Influencing Therapeutic Outcomes of Patients Taking NHPs
One of the most important reasons why studies investigating the potential therapeutic role of NHPs are often inconsistent is the large number of variables that can influence clinical outcomes.Different study design and follow-up, enrolled patients' characteristics, NHP dosing and formulation, concomitant treatments, and outcome measures are just some of them.
For example, with regard to the potential effects of vitamin D, the 25(OH)D level (< vs. >10 ng/dL) must be taken into account [137].Morelli et al. conducted a very interesting study to assess the actual role of vitamin D in CCR, taking into account a number of potential predictors of deficiency in this micronutrient.First, they found that OS in patients with 25(OH)D > 10 ng/mL was longer compared to patients with lower levels (<10 ng/mL).Subsequently, when examining other variables, including hematological parameters, the neutrophil-to-lymphocyte ratio (NLR) was found to be the most powerful predictor of vitamin D deficiency.When NLR and 25(OH)D levels were considered simultaneously, patients with NLR < 3.5 plus 25(OH)D > 10 ng/mL had a longer OS than NLR > 3.5 plus 25(OH)D < 10 ng/mL (p = 0.0004) [137].
Several clinical studies have examined how dietary vitamin D intake affects the intestinal bacterial composition resulting in anti-inflammatory potential [138,139], and the role of vitamin D on the modulation of the gut microbiota; consequently, the possible effect of supplementation in patients with CRC have been extensively investigated [139][140][141][142]. Women seem to have lower vitamin D absorption than men, due to a different metabolism and the presence of hormones influencing different bacterial species in the microbiota [143].A randomized phase II clinical trial showed that CRC patients who took 2000 IU of vitamin D daily for one year experienced a change in their gut microbiota and amino acid biosynthetic pathways.Although this study was conducted on only 60 patients, it showed that women (n.30/60) taking the supplement had lower vitamin D levels at baseline than men and that supplementation closed this gap [100].Sex/gender may also influence the effects of other vitamins.Mooney et al. examined the potential of vitamin supplementation [500 mg vitamin C and 400 IU vitamin E per day] in men and women who smoke at least 10 cigarettes per day in reducing benzo(a)pyrene [B(a)P] adducts, a well-established marker of cancer risk [144].No treatment benefits were found in the entire study population and among men, whereas in women B(a)P-DNA adducts decreased by 31% compared to placebo (p = 0.03).
Hercberg et al. performed an RCT within the framework of 'The Supplementation in Vitamins and Mineral Antioxidants' (SU.VI.MAX) study to evaluate the effect of daily supplementation of vitamins and minerals (120 mg of vitamin C, 30 mg of vitamin E, 6 mg of β-carotene, 100 µg of selenium and 20 mg of zinc) in reducing the risk of skin cancer (SC) in a large sample of volunteers (7876 women and 5141 men) followed for 7.5 years.No difference was found in SC frequency among men, whereas the incidence of SC (including melanoma) in women was higher in women who received supplementation (HR= 1.68; p = 0.03) compared to placebo [145].Overall, these results suggest that further clinical investigations, with a larger number of patients and appropriate stratification according to several covariates, including sex/gender, are needed to clarify the potential beneficial effect of vitamin supplementation against cancer.
Another issue is ascribed to the specific properties of NHPs, but also to epigenetic modifications possibly induced.A phase 3 RCT, the 'Oral Nicotinamide to Reduce Actinic Cancer' (ONTRAC), demonstrated that 500 mg nicotinamide (NAM) twice daily is safe and effective in preventing nonmelanoma SC and reducing the number of actinic keratosis in high-risk patients.Notably, while the number of actinic keratosis was reduced as early as 3 months and further at 6, 9 and 12 months, positive results regarding cancer lesions were found after a 12-month treatment but not after a shorter period.These beneficial effects were lost after NAM discontinuation [146].
NAM, as a component of ARCON (carbogen + NAM), has been also recognized as valuable treatment for head and neck, bladder [147] and laryngeal neoplasms [148].Compared with accelerated radiotherapy (AR) only, ARCON reduced local relapse rate and improved bladder conservation rate and OS in patients with stage II-to-IV laryngeal cancer.However, such benefits were found only in hypoxic tumors and not in those which were well oxygenated [148].
Hypoxic changes are strongly correlated with changes in microenvironment and tumor metabolism, including modulation of the oxidative state and, more properly, redox homeostasis.This is another very important aspect, since ROS, when produced in excess of the antioxidant molecules, induce dysfunction of molecular mechanisms crucial for cellular defense and maintenance of redox balance, causing chronic oxidative stress and inflammation, which characterize age-associated diseases [149][150][151][152], and promote DNA damage and carcinogenesis [153].
Indeed, NHPs could exert anticancer effects mainly due to their antioxidant and anti-inflammatory characteristics and their ability to stimulate the activation of enzymes essential for the regulation of oxidative and inflammatory homeostasis [154], also helping to overcome the effects of chemotherapy-induced oxidative stress in cancer patients [155].
Given the wide use of NHPs in the general population and in cancer patients [156], an important issue currently being debated is the inter-individual variability in the magnitude of effects (both beneficial and adverse) due to NHP-drug interactions.
This aspect is crucial, considering that a significant proportion of cancer patients take NHPs during cancer treatment without the knowledge of their physicians [157,158] and supplement-drug interactions may led to adverse events associated to pharmacokinetic and pharmacodynamic interactions due to a possible alteration of the efficacy and safety profiles of anticancer drugs [158].

Conclusions
Some RCTs studying the effects of silymarin (topical and oral), ginsenoside (oral), and oral vitamin E (alone or combined with other NHPs) might be useful against adverse events related to radiotherapy or chemotherapy with capecitabine or treatment with doxorubicin alone or combined with paclitaxel and cyclophosphamide.Curcumin (topical and oral) and lycopene (oral) could provide some benefit in patients with prostate cancer by reducing PSA levels.
Overall, the results of available RCTs do not allow significant conclusions to be drawn about the role of NHPs in cancer.Notably, there are conflicting results among in vitro studies that show clear beneficial effects of NHPs in influencing inflammatory and oxidative status, survival, and proliferation of cancer cells and RCTs that, in contrast, have often found little or no benefit for cancer patient survival and therapy-related adverse effects.Moreover, although NHPs have relatively low toxicity, their wide use among cancer patients, often without the knowledge of treating physicians, also creates concern.Further large RCTs are needed to determine precise indications and the correct route and timing of administration before considering the addition of NHPs to clinical practice.

Figure 1 .
Figure 1.Mechanisms of anti-cancer action and radio-chemo immune protection of chemica isolated from Natural Health Products to improve the efficacy of cancer therapy and mitigate side events.

Figure 1 .
Figure 1.Mechanisms of anti-cancer action and radio-chemo immune protection of chemical classes isolated from Natural Health Products to improve the efficacy of cancer therapy and mitigate related side events.

Table 1 .
Characteristics and main results of RCTs available in the literature over the past two decades that have tested the effects of herbal supplements in different types of cancer.
The application of silymarin gel 1% twice a day may reduce the severity of capecitabine-induced Hand-Foot syndrome and delay its occurrence.

Table 2 .
Characteristics and main results of RCTs available in the literature over the past two decades that have tested the effects of vitamins and other micronutrients in different types of cancer.